For patients with locally advanced resectable gastric or gastroesophageal junction adenocarcinoma, perioperative FLOT is an established standard treatment approach. The phase 3 MATTERHORN trial investigated whether adding durvalumab to this regimen could further improve outcomes, and this report provides the final overall survival analysis together with event-free survival analyses according to pathological response and nodal status.
The article titled “Perioperative durvalumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable gastric and gastro-oesophageal junction adenocarcinoma (MATTERHORN): final results of overall survival and event-free survival by pathological response in a global, randomised, double-blind, placebo-controlled, multicentre, phase 3 trial” was published on September 9, 2026, in The Lancet.
Authors: Yelena Y. Janjigian, Salah-Eddin Al-Batran, Zev A. Wainberg, Kei Muro, Daniela Molena, Eric Van Cutsem, Woo Jin Hyung, Lucjan Wyrwicz, Do-Youn Oh, Takeshi Omori, Markus Moehler, Arinilda C. Bragagnoli, Gabriel Garbaos, Moishe Liberman, María Luisa Limón Mirón, Elizabeth C. Smyth, Lin-Yang Cheng, Scott H. Robbins, Nicola Valeri, Ioannis Xynos, and Josep Tabernero, on behalf of the MATTERHORN investigators.
About the MATTERHORN Trial
MATTERHORN is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 trial conducted at 147 medical centers across 20 countries.
Eligible patients were adults with previously untreated, histologically confirmed stage II–IVa resectable gastric or gastroesophageal junction adenocarcinoma who were candidates for radical surgery. Patients were required to have an ECOG performance status of 0 or 1, adequate organ and bone marrow function, and tumor tissue available for PD-L1 assessment. Patients with peritoneal dissemination or distant metastases were excluded.
Between November 17, 2020, and September 2, 2022, 1,258 patients were enrolled, of whom 948 were randomly assigned in a 1:1 ratio to durvalumab plus FLOT or placebo plus FLOT. Each group included 474 patients.
The median age of the overall population was 62 years. Gastric tumors accounted for 68% of primary tumors, while 32% were located at the gastroesophageal junction. Seventy percent of patients had clinically node-positive disease, and 90% had PD-L1 tumor area positivity of at least 1%.
Patients received durvalumab 1,500 mg or placebo intravenously every 4 weeks together with FLOT administered every 2 weeks on days 1 and 15 of each cycle. Treatment included two neoadjuvant cycles followed by surgery and two adjuvant cycles. After completion of FLOT, patients continued durvalumab or placebo every 4 weeks for 10 additional cycles. Surgery was planned 4–8 weeks after the final dose of neoadjuvant treatment.
The primary endpoint was event-free survival, while overall survival was a key secondary endpoint. Previous MATTERHORN results showed that durvalumab plus FLOT significantly improved event-free survival compared with placebo plus FLOT, with an HR of 0.71 (95% CI 0.58–0.86; p<0.001). Pathological complete response in the intention-to-treat population was also higher with durvalumab plus FLOT, at 19% versus 7%.
Final Overall Survival Results
At the final overall survival analysis, 160 of 474 patients in the durvalumab group and 192 of 474 patients in the placebo group had died. Durvalumab plus FLOT significantly improved overall survival compared with placebo plus FLOT, with an HR of 0.78 (95% CI 0.63–0.96; p=0.021). Median overall survival had not been reached in either treatment group. At 24 months, the overall survival rate was 76% in the durvalumab group compared with 70% in the placebo group. At 36 months, the corresponding rates were 69% and 62%.
The overall survival benefit in the population excluding patients with microsatellite instability-high tumors was consistent with that observed in the intention-to-treat population. Overall survival favored durvalumab across most clinically relevant subgroups, although MATTERHORN was not powered for individual subgroup comparisons.
Among patients with clinically node-positive disease, the HR for overall survival was 0.73 (95% CI 0.57–0.94). In patients with node-negative disease, the HR was 1.01 (95% CI 0.67–1.51). However, the interaction between treatment and clinical lymph node status was not statistically significant. Among patients with PD-L1 tumor area positivity of at least 1%, the HR for overall survival was 0.79 (95% CI 0.63–0.99). In those with PD-L1 TAP below 1%, the HR was also 0.79, with a wider 95% CI of 0.41–1.50.
In a post-hoc exploratory analysis by histological subtype, the HR was 0.76 in patients with intestinal histology, 0.61 in those with indeterminate histology, and 0.98 in patients with diffuse histology. Histological subtype, however, was not centrally confirmed, and these findings should be interpreted cautiously.
Pathological Response and Event-Free Survival
The investigators also examined event-free survival according to pathological response. Among patients who underwent surgery and had specimens evaluable by central pathology review, pathological complete response was achieved in 91 of 385 patients, or 24%, in the durvalumab group compared with 34 of 372 patients, or 9%, in the placebo group.
Major pathological response was observed in 33% versus 18%, while any pathological response was reported in 90% versus 84%, respectively. Event-free survival numerically favored durvalumab plus FLOT among patients who achieved pathological complete response, with an HR of 0.29 (95% CI 0.08–0.96). The HR was 0.32 (95% CI 0.15–0.68) among patients with major pathological response and 0.60 (95% CI 0.46–0.79) among those with any pathological response.
Among patients with no pathological response, the EFS HR for durvalumab plus FLOT versus placebo plus FLOT was 1.27 (95% CI 0.71–2.25). These analyses were post-hoc and exploratory and were limited to patients who underwent surgery and had specimens available for evaluation. These pCR results should be distinguished from the previously reported ITT rates of 19% and 7%, respectively.
Nodal Status After Surgery
Durvalumab plus FLOT was also associated with a higher proportion of patients having no nodal involvement at surgery. Among patients evaluable for nodal status, 239 of 411 patients, or 58%, in the durvalumab group had no nodal involvement compared with 179 of 400 patients, or 45%, in the placebo group.
Downstaging to node-negative disease occurred in 36% of patients receiving durvalumab plus FLOT and 28% receiving placebo plus FLOT. Event-free survival numerically favored durvalumab in both patients without nodal involvement and those with nodal involvement, with HRs of 0.74 and 0.77, respectively.
Safety
The safety profile remained consistent with the previously reported MATTERHORN findings. Grade 3 or 4 adverse events occurred in 72% of patients receiving durvalumab plus FLOT and 71% receiving placebo plus FLOT. Serious adverse events were reported in 48% and 44% of patients, respectively.
Adverse events leading to discontinuation of any trial treatment occurred in 30% of patients in the durvalumab group and 23% in the placebo group. Immune-mediated adverse events of any grade were more common with durvalumab, occurring in 23% of patients compared with 7% in the placebo group. Grade 3 or 4 immune-mediated adverse events occurred in 7% versus 4%, respectively.
Adverse events with an outcome of death that were considered possibly related to any trial treatment occurred in six patients, or 1%, receiving durvalumab plus FLOT and two patients, or less than 1%, receiving placebo plus FLOT.
The addition of durvalumab did not compromise surgical feasibility. Adverse events resulted in surgery not being performed in three patients in the durvalumab group and two patients in the placebo group. Adverse events delayed surgery in 2% and 3% of patients, respectively. Among patients who completed surgery, complete resection was achieved in 92% in both groups.
Study Limitations
The authors noted several limitations. Histological subtype, including diffuse histology, was not centrally confirmed, and clinical nodal status was determined by investigators. Endoscopic ultrasonography and diagnostic laparoscopy were not mandated for staging.
The analyses of event-free survival according to pathological response and nodal status were post-hoc and exploratory and included only patients who completed surgery. This population would be expected to have a more favorable prognosis than the overall randomized population, limiting direct comparisons with intention-to-treat results.
Pathological response was assessed using the modified Ryan criteria, which are not universally used. In addition, MATTERHORN did not enroll patients from several countries and regions with high incidences of gastric and gastroesophageal junction adenocarcinoma, including China, and Black patients were underrepresented.
Conclusion
The final overall survival analysis of MATTERHORN demonstrated that perioperative durvalumab plus FLOT significantly improved overall survival compared with placebo plus FLOT in patients with resectable gastric or gastroesophageal junction adenocarcinoma.
Together with the previously reported improvement in event-free survival and pathological complete response, the findings support perioperative durvalumab plus FLOT as a new standard treatment option for patients with resectable gastric or gastroesophageal junction adenocarcinoma.
The full article is available in The Lancet.
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